The involvement of Parkin-dependent mitophagy in the anti-cancer activity of Ginsenoside

Xin Sun; Yeting Hong; Yuhan Shu; Caixia Wu; Guiqin Ye; Hanxiao Chen; Hongying Zhou; Ruilan Gao; Jianbin Zhang

doi:10.1016/j.jgr.2021.06.009

The involvement of Parkin-dependent mitophagy in the anti-cancer activity of Ginsenoside

J Ginseng Res. 2022 Mar;46(2):266-274. doi: 10.1016/j.jgr.2021.06.009. Epub 2021 Jul 8.

Authors

Xin Sun¹, Yeting Hong², Yuhan Shu³, Caixia Wu⁴, Guiqin Ye², Hanxiao Chen⁵, Hongying Zhou¹, Ruilan Gao⁶, Jianbin Zhang⁴

Affiliations

¹ Department of Oncology, Cancer Center of Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
² Hangzhou Medical College, Hangzhou, China.
³ College of Biomedical Engineering & Instrument Science, Zhejiang University, Hangzhou, China.
⁴ Clinical Research Institute, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, People's Hospital of Hangzhou Medical College, Hangzhou, China.
⁵ Wenzhou Medical University, Wenzhou, China.
⁶ Institution of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Abstract

Colon cancer, the third most frequent occurred cancer, has high mortality and extremely poor prognosis. Ginsenoside, the active components of traditional Chinese herbal medicine Panax ginseng, exerts antitumor effect in various cancers, including colon cancer. However, the detailed molecular mechanism of Ginsenoside in the tumor suppression have not been fully elucidated. Here, we chose the representative ginsenoside Rg3 and reported for the first time that Rg3 induces mitophagy in human colon cancer cells, which is responsible for its anticancer effect. Rg3 treatment leads to mitochondria damage and the formation of mitophagosome; when autophagy is inhibited, the clearance of damaged mitochondria can be reversed. Next, our results showed that Rg3 treatment activates the PINK1-Parkin signaling pathway and recruits Parkin and ubiquitin proteins to mitochondria to induce mitophagy. GO analysis of Parkin targets showed that Parkin interacts with a large number of mitochondrial proteins and regulates the molecular function of mitochondria. The cellular energy metabolism enzyme GAPDH is validated as a novel substrate of Parkin, which is ubiquitinated by Parkin. Moreover, GAPDH participates in the Rg3-induced mitophagy and regulates the translocation of Parkin to mitochondria. Functionally, Rg3 exerts the inhibitory effect through regulating the nonglycolytic activity of GAPDH, which could be associated with the cellular oxidative stress. Thus, our results revealed GAPDH ubiquitination by Parkin as a crucial mechanism for mitophagy induction that contributes to the tumor-suppressive function of ginsenoside, which could be a novel treatment strategy for colon cancer.

Keywords: BNIP3, BCL2 interacting protein 3; COX Ⅳ, cytochrome c oxidase Ⅳ; GAPDH; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GSH, glutathione; Gensinoside; HSP60, heat shock protein 60 KDa; LC3, microtubule-associated proteins 1A/1B light chain 3; MFN2, mitofusion 2; Mitophagy; PARK2, Parkin; PHGDH, phosphoglycerate dehydrogenase; PINK1, PTEN induced putative kinase 1; Parkin; ROS; SQSTM1, sequestosome 1; TIM23, translocase of the inner membrane 23; TOMM20, translocase of outer mitochondrial membrane 20; Ubiquitination; VDAC1, voltage-dependent anion-selective channel protein 1.